This invention relates to compounds which are antagonists of the progesterone receptor, their preparation and utility.
Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as antagonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Described by Jones, et al, (U.S. Pat. No. 5,688,810) is the PR antagonist dihydroquinoline A.

Jones, et al. described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand.

Jones, et al. described compound C (U.S. Pat. No. 5,696,127) as a PR ligand.

Zhi, et al. described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998).

Zhi, et al. described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998).

Combs, et al. disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995).

Perlman, et al. described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994).

Hamann, et al. described the PR antagonist J (Ann. N.Y. Acad. Sci., 761, 383, 1995).

Chen, et al. described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997).

Kurihari, et. al. described the PR ligand L (J. Antibiotics, 50, 360, 1997).

Kuhla, et al. disclosed the oxindole M as having cardiotonic activity (WO 86/03749).

Weber teaches the oxindole N for cardiovascular indications (WO 91/06545).

Fischer, et al. describe a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516).

Singh, et al. described the PDE III inhibitor P (J. Med. Chem., 37, 248, 1994).

Andreani, et al. described the cytotoxic agent Q (Acta. Pharn. Nord., 2, 407, 1990).

Binder, et al. described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767).

Walsh described the oxindole S as an intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566).

Bohm, et al. claim the oxindole T as cardiovascular agents (WO 91/06545).

Bohm, et al. include the generic structure U (WO 91/04974).

JP 63112584 A contains the generic structure V:

Boar, et al. described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).

Kende, et al. described methodology for preparing 3,3-substituted oxindoles, e.g. X, that was utilized in the present invention (Synth. Commun., 12, 1, 1982).
